Selective Inhibitors of Nuclear Factor KappaB Activation and Uses Thereof

Abstract

The present invention provides cell permeable NF-κB inhibitors consist of a polypeptide derived from the p65 subunit of NF-κB and a protein transduction domain derived from antennapedia third helix sequence. The inhibitor suppressed NF-κB activation induced by TNF, LPS, IL-1, okadaic acid, PMA, H 2 O 2 and cigarette smoke condensate. NF-κB-regulated reporter gene expression induced by TNF, TNFR1, TRADD, TRAF2, NIK, IKK and p65 was suppressed by the inhibitor. The inhibitor enhanced TNF- and chemotherapeutic agent-induced apoptosis. Overall these results demonstrate a NF-κB inhibitor that can selectively inhibit NF-κB activation induced by various inflammatory stimuli, down-regulate NF-κB mediated gene expression and upregulate apoptosis.

1 - 14 . (canceled) 
     
     
         15 . A method of treating cancer in an individual, comprising the step of administering to the individual a composition comprising:
 (a) a polypeptide comprising (i) a sequence selected from the group consisting of SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7 SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:12 and SEQ ID NO:13; and (ii) a transduction sequence selected from the group consisting of SEQ ID NO:3, a herpes virus structural protein transduction sequence, and HIV tat protein; and   (b) a pharmaceutically acceptable carrier.   
     
     
         16 . The method of  claim 15 , further comprising the step of administering to said individual a chemotherapeutic agent. 
     
     
         17 . The method of  claim 16 , wherein the chemotherapeutic agent is doxorubicin or cisplatin. 
     
     
         18 . The method of  claim 15 , wherein the cancer is metastatic cancer. 
     
     
         19 . The method of  claim 15 , wherein the composition is administered intraperitoneally, intramuscularly, subcutaneously, intravenously, or orally. 
     
     
         20 . The method of  claim 15 , wherein the polypeptide comprises SEQ ID NO:5. 
     
     
         21 . The method of  claim 15 , wherein the polypeptide comprises SEQ ID NO:6. 
     
     
         22 . The method of  claim 15 , wherein the polypeptide comprises SEQ ID NO:7. 
     
     
         23 . The method of  claim 15 , wherein the polypeptide comprises SEQ ID NO:8. 
     
     
         24 . The method of  claim 15 , wherein the polypeptide comprises SEQ ID NO:9. 
     
     
         25 . The method of  claim 15 , wherein the polypeptide comprises SEQ ID NO:11. 
     
     
         26 . The method of  claim 15 , wherein the polypeptide comprises SEQ ID NO:12. 
     
     
         27 . The method of  claim 15 , wherein the polypeptide comprises SEQ ID NO:13. 
     
     
         28 . The method of  claim 15 , wherein the transduction sequence is SEQ ID NO:3. 
     
     
         29 . The method of  claim 15 , wherein the transduction sequence is a herpes virus structural protein transduction sequence. 
     
     
         30 . The method of  claim 15 , wherein the transduction sequence is HIV tat protein. 
     
     
         31 . The method of  claim 15 , wherein the polypeptide consists of (i) a sequence selected from the group consisting of SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:12 and SEQ ID NO:13; and (ii) a transduction sequence selected from the group consisting of SEQ ID NO:3, a herpes virus structural protein transduction sequence, and HIV tat protein. 
     
     
         32 . The method of  claim 31 , wherein the transduction sequence is SEQ ID NO:3. 
     
     
         33 . The method of  claim 31 , wherein the transduction sequence is a herpes virus structural protein transduction sequence. 
     
     
         34 . The method of  claim 31 , wherein the transduction sequence is HIV tat protein. 
     
     
         35 . A method of treating cancer in an individual, comprising the step of administering to the individual a composition comprising:
 (a) a polypeptide comprising SEQ ID NO:4 or SEQ ID NO:10; and   (b) a pharmaceutically acceptable carrier.   
     
     
         36 . The method of  claim 35 , wherein the polypeptide comprises SEQ ID NO:4. 
     
     
         37 . The method of  claim 35 , wherein the polypeptide comprises SEQ ID NO:10. 
     
     
         38 . The method of  claim 35 , wherein the polypeptide consists of SEQ ID NO:4. 
     
     
         39 . The method of  claim 35 , wherein the polypeptide consists of SEQ ID NO:10. 
     
     
         40 . The method of  claim 35 , further comprising the step of administering to said individual a chemotherapeutic agent. 
     
     
         41 . The method of  claim 40 , wherein the chemotherapeutic agent is doxorubicin or cisplatin. 
     
     
         42 . The method of  claim 35 , wherein the cancer is metastatic cancer. 
     
     
         43 . The method of  claim 35 , wherein the composition is administered intraperitoneally, intramuscularly, subcutaneously, intravenously, or orally.